The impact of PPARalpha activation on whole genome gene expression in human precision cut liver slices
SourceBMC Genomics, 16, 1, (2015), pp. 760
Article / Letter to editor
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SubjectRadboudumc 11: Renal disorders RIMLS: Radboud Institute for Molecular Life Sciences
BACKGROUND: Studies in mice have shown that PPARalpha is an important regulator of lipid metabolism in liver and key transcription factor involved in the adaptive response to fasting. However, much less is known about the role of PPARalpha in human liver. METHODS: Here we set out to study the function of PPARalpha in human liver via analysis of whole genome gene regulation in human liver slices treated with the PPARalpha agonist Wy14643. RESULTS: Quantitative PCR indicated that PPARalpha is well expressed in human liver and human liver slices and that the classical PPARalpha targets PLIN2, VLDLR, ANGPTL4, CPT1A and PDK4 are robustly induced by PPARalpha activation. Transcriptomics analysis indicated that 617 genes were upregulated and 665 genes were downregulated by PPARalpha activation (q value < 0.05). Many genes induced by PPARalpha activation were involved in lipid metabolism (ACSL5, AGPAT9, FADS1, SLC27A4), xenobiotic metabolism (POR, ABCC2, CYP3A5) or the unfolded protein response, whereas most of the downregulated genes were involved in immune-related pathways. Among the most highly repressed genes upon PPARalpha activation were several chemokines (e.g. CXCL9-11, CCL8, CX3CL1, CXCL6), interferon gamma-induced genes (e.g. IFITM1, IFIT1, IFIT2, IFIT3) and numerous other immune-related genes (e.g. TLR3, NOS2, and LCN2). Comparative analysis of gene regulation by Wy14643 between human liver slices and primary human hepatocytes showed that down-regulation of gene expression by PPARalpha is much better captured by liver slices as compared to primary hepatocytes. In particular, PPARalpha activation markedly suppressed immunity/inflammation-related genes in human liver slices but not in primary hepatocytes. Finally, several putative new target genes of PPARalpha were identified that were commonly induced by PPARalpha activation in the two human liver model systems, including TSKU, RHOF, CA12 and VSIG10L. CONCLUSION: Our paper demonstrates the suitability and superiority of human liver slices over primary hepatocytes for studying the functional role of PPARalpha in human liver. Our data underscore the major role of PPARalpha in regulation of hepatic lipid and xenobiotic metabolism in human liver and reveal a marked immuno-suppressive/anti-inflammatory effect of PPARalpha in human liver slices that may be therapeutically relevant for non-alcoholic fatty liver disease.
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